A 3-week-old boy, former 39-week term infant, presented to the emergency department with a rash. One week before presentation, he developed dark, purple papules on his forehead, which then spread to the abdomen and inguinal regions. Throughout this time, he was eating well, gaining weight, developing appropriately, and was afebrile without cough, congestion, or rhinorrhea. On presentation, the patient was well appearing with normal vital signs. His weight was 4.83 kg (86th percentile for age), his length was 56 cm (47th percentile for age), and his head circumference was 37 cm (62nd percentile for age). On skin examination, there were scattered purpuric papules and macules on the scalp, forehead, trunk, abdomen, and inguinal region. Initial laboratory studies were remarkable only for mild anemia. Our expert panel examines the case, offers a differential for a child with a “blueberry muffin” rash, and makes diagnostic considerations.
- AML —
- acute myeloid leukemia
- CMV —
- CNS —
- central nervous system
- CRS —
- congenital rubella syndrome
- ED —
- emergency department
- HVA —
- homovanillic acid
- Ig —
- LCH —
- Langerhans cell histiocytosis
- TORCH —
- toxoplasmosis, other (syphilis, varicella-zoster, parvovirus B19), rubella, cytomegalovirus, and herpes
- VMA —
- vanillylmandelic acid
Case History With Subspecialty Input
Dr Gregory Valentine (Resident, Pediatrics, Global Child Health)
A 3-week-old boy, former 39-week term infant, presented to the emergency department (ED) with a rash. One week before presentation, he developed dark, purple papules on his forehead, which then spread to the abdomen and inguinal regions. Over the course of a week, the rash continued to spread and appeared to be on the extremities, abdomen, and head, which prompted presentation to the ED. From the time of onset of the rash to the presentation at the ED, he was eating well, gaining weight, developing appropriately, and had remained afebrile without cough, congestion, or rhinorrhea.
Regarding birth history, the patient was born to a gravida 3 para 3 mother who had prenatal care beginning in the first trimester and no reported complications during pregnancy or delivery. He passed his hearing screen, and the mother’s serologies were negative, including group B Streptococcus. Additionally, both newborn screens were normal, and he received the hepatitis B vaccine at birth.
The patient had 2 healthy older siblings who did not have a similar rash in the first few months of their lives. The family had not traveled to any other country since his birth, and there were no animal exposures. The patient was seen by his pediatrician on the day of presentation, who referred him to be evaluated in the ED.
In the ED, the patient was well appearing with a temperature of 98.0° F, a pulse of 156 beats per minute, blood pressure of 87/52 mm Hg, and a respiratory rate of 40 breaths per minute. His weight was 4.83 kg (86th percentile for age), his length was 56 cm (47th percentile for age), and his head circumference was 37 cm (62nd percentile for age). He was in no acute distress. He had no discernible petechiae, but he had scattered, ecchymotic, purpuric papules and macules on the scalp, forehead, trunk, abdomen, and inguinal region (Figs 1 and 2).
Results of the patient’s laboratory evaluation are shown in Table 1. They are notable for a mild anemia but otherwise are unremarkable. Cerebral spinal fluid studies, liver function tests, chest radiograph, and coagulation studies were interpreted as normal. A head ultrasound was significant for visualization of lenticulostriate vessels, consistent with mineralizing vasculopathy, a nonspecific finding that can be seen with in utero infection. The patient was admitted for additional evaluation and management.
Dr John Darby (Moderator, Pediatric Hospital Medicine)
Does this patient qualify as having a “blueberry muffin” rash and, if so, what is the differential diagnosis?
Dr Gerardo Cabrera-Meza (Neonatology)
Yes, the description is consistent with a blueberry muffin rash. The term originated in the early 1960s when the rubella epidemic occurred in this country. This rash occurs because of extramedullary hematopoiesis in sites of different magnitudes and extensions. Since then, the differential diagnosis associated with this type of rash has been broadened significantly. The differential includes the following: infectious etiologies, such as toxoplasmosis, other (syphilis, varicella-zoster, parvovirus B19), rubella, cytomegalovirus, and herpes (TORCH) infections (especially congenital rubella), blood dyscrasias (ABO incompatibility, Rh incompatibility, minor group incompatibility, twin-to-twin transfusion syndrome), malignancies (congenital leukemia, Langerhans cell histiocytosis [LCH], neuroblastoma), and skin disorders (hemangiomatosis, blue rubber bleb nevus syndrome).
Cytomegalovirus (CMV) is the most common congenital infection and can cause a petechial rash due to thrombocytopenia. Congenital toxoplasmosis has been described with this type of rash, but it is a rare infection in the United States. Syphilis is another possibility.
Dr Cabrera-Meza mentioned several infectious causes of a purpuric rash. With TORCH infections, do you typically see a purpuric rash presenting at birth or several weeks later?
Dr Mary Healy (Pediatric Infectious Disease)
In an infant with a purpuric rash, as mentioned by Dr Cabrera-Meza, you need to think broadly because some infections presenting with this type of rash need to be treated promptly. However, in this case, the infant has been perfectly well until this point, and the rash did not develop until several weeks after birth. This makes TORCH infections less likely, but not impossible.
Without the history above, the appearance of the rash alone would lead me to consider the blueberry muffin rash characteristic of congenital rubella syndrome (CRS). However, CRS is rare in the United States and in other developed countries with high uptake of childhood vaccination. Between 2004 and 2012, there were only 6 reported cases to the Centers for Disease Control and Prevention.1 Virtually all of these cases were in infants of unimmunized mothers or were imported cases, meaning that they were from people that were not immunized and came to the United States from another country.
In this case, the infant’s mother has had 3 children all born within 5 to 6 years of each other and has had medically attended deliveries in US hospitals each time with multiple screenings for infectious diseases during each pregnancy. It is highly unlikely she would have tested rubella nonimmune and not have received the measles, mumps, rubella vaccine postdelivery.
Also, the clinical presentation of CRS is not subtle. There were no other indications of CRS in this infant, specifically, there was no hepatosplenomegaly, no chorioretinitis, no transaminitis, a history of a normal hearing screen, and he was normocephalic. For these reasons, despite the appearance of the rash, I felt strongly that this was not going to be CRS.
And what about congenital toxoplasmosis or syphilis as mentioned previously? Can they present like this?
It is rare that we see the full clinical syndrome of congenital toxoplasmosis because 80% to 90% of infected infants are asymptomatic at birth. The classic presentation is a triad of intracranial calcifications, chorioretinitis, and hydrocephalus, which may occur if a mother is infected early in the pregnancy. However, this is rare. The vast majority of these patients are diagnosed months or years later when they present with, for example, poor visual acuity early in childhood and are found to have chorioretinitis, or perhaps hearing problems or developmental delay. The cutaneous findings may be diverse, including a maculopapular, blue, or petechial rash secondary to thrombocytopenia.2 It is noteworthy that this infant had a normal platelet count.
Congenital syphilis could also present with a rash at this age. However, the rash is typically different. Our patient did not have any rash on the palms or soles, and congenital syphilis does not give you the typical blueberry muffin type of rash. Cutaneous findings are usually maculopapular lesions prominent on the palms, soles, back, buttocks, and posterior thighs, as well as vesiculobullous lesions, starting as hyperpigmented red papules and progressing to desquamation and crusting.3,4
It important to rule these infections out, however, because left untreated, both infections can have severe and long-term sequelae, such as impairment of vision and hearing and developmental delay with congenital toxoplasmosis and multiorgan involvement of the central nervous system (CNS), bones and joints, teeth, eyes, ears, and skin in congenital syphilis, some of which may take decades to manifest. After treatment, both conditions require follow-up to ensure relapses do not occur.5,6
And is congenital CMV a consideration?
After examining this infant, I felt that congenital CMV was unlikely. In common with congenital toxoplasmosis, the majority of congenital CMV infections are subclinical at birth or in the neonatal period. When present, symptoms and signs of congenital CMV include small for gestational age, jaundice, hepatosplenomegaly, neurologic manifestations, including microcephaly and hypotonia, and a rash. Pinpoint petechiae are more characteristic of the rash of congenital CMV, rather than a blueberry muffin–type appearance. Also, thrombocytopenia is associated with this rash.
Although unlikely, congenital CMV should also be ruled out because neonates with symptomatic congenital infection, with or without CNS involvement, have improved hearing and neurodevelopmental outcomes at 2 years of age when treated with valganciclovir for 6 months. The American Academy of Pediatrics does not recommend antiviral therapy for asymptomatic infants at this time, however, at a minimum, these infants should be monitored for the development of hearing loss over time.7
Oncologic causes of this rash were in the differential diagnosis. What were your thoughts when you saw this patient?
Dr Wendy Allen-Rhoades (Pediatric Oncology)
Oncologic diagnoses in a newborn are certainly rare, but they are important to consider in this case. One of the most common oncologic diagnoses in the newborn period that can present with a rash is congenital neuroblastoma. Furthermore, neuroblastoma is the most common extracranial solid tumor in childhood and “4S” is a special stage of neuroblastoma in infants <1 year of age with metastases limited to the liver, bone marrow, and/or skin.8 The rash secondary to skin metastases in neuroblastoma typically consists of generalized, scattered, small (<2 cm), firm, nontender blue, red, or purple papules and/or mobile subcutaneous nodules.9
Adrenal and hepatic neuroblastoma lesions can be incidentally detected on routine prenatal ultrasounds. These incidentally noted lesions in neonates can usually be monitored postnatally, under an oncologist’s supervision, with serial ultrasounds, and many of them self-resolve without treatment. However, sometimes the lesions progress or are too large for “watchful waiting” and require a biopsy and/or resection with subsequent chemotherapy treatment. Additionally, some patients who have liver involvement can become ill quickly and require prompt therapy. Overall, however, most patients with neuroblastoma in the neonatal period do well, even with metastases to those restricted sites. The mother did not recall any specific mention of abnormalities on prenatal ultrasounds, and an abdominal ultrasound was performed to evaluate the adrenal glands and liver.
Leukemia cutis, which is leukemia in the skin, is another oncologic diagnosis that can present with a skin rash in the newborn period. Although the blood counts and peripheral smear were normal in this patient except for a mild anemia, it does not rule out leukemia. It is not uncommon to have relatively normal counts early in the course of acute leukemia. Additionally, the presence of peripheral blasts is not necessary to make a diagnosis of leukemia, because the bone marrow can be involved with blasts without spillage into the peripheral blood. Finally, LCH, a rare histiocytic disorder, can present in a multitude of ways, including various skin findings. Specifically, infants may present with skin lesions that are brownish purple papules of the skin.
So, we’ve considered infectious and oncologic causes and the differential remains broad. Dr Hunt, are there dermatologic conditions we should consider, and can you help us narrow the possibilities at all based on the features of this skin rash?
Dr Raegan Hunt (Pediatric Dermatology)
It is hard to narrow the differential diagnosis based on this patient’s skin exam alone. I agree that the 2- to 10-mm, nonblanching, magenta-to-violaceous macules and thin papules seen in this patient are consistent with a blueberry muffin rash. Regarding the differential diagnosis previously discussed, the individual lesions are not as sharply circumscribed and not as intensely red or purple, respectively, as those typically seen in hemangiomatosis or blue rubber bleb nevus syndrome. Due to its clinical appearance, the blueberry muffin rash is included in the broad category of neonatal purpura, yet, in contrast to traditional purpuric skin disorders caused by extravasation of red blood cells into the skin, in blueberry muffin rash cases, the purpuric-to-violaceous appearance is due to either extramedullary hematopoiesis in the skin or metastatic dermal infiltration of malignant neoplastic cells.10 This patient had numerous flat-to-mildly indurated, small skin lesions. This eruption localized mostly to the face and scalp and involved the trunk to a lesser extent. Remarkably, the extremities were spared in this child. The classic description of a blueberry muffin rash in a TORCH infection has more widespread lesions. In addition, malignancy-related skin metastases in a newborn blueberry muffin rash are typically described as firmer, larger, and fewer.
Unfortunately, no clues led to a certain diagnosis. Interestingly, lenticulostriate vasculopathy was found on head ultrasound. This is a nonspecific CNS imaging finding that has been associated with congenital infections, neonatal lupus, as well as intrauterine exposures and genetic conditions, but not with neonatal malignancies.11 As mentioned, initially there was concern for a TORCH infection based on the skin findings, but it didn’t seem to fit well because the child was healthy appearing, had good prenatal care, and the skin lesions were not present until ∼3 weeks of life. Unusual purpuric variants of neonatal lupus have been reported, and neonatal lupus tends to manifest with lesions concentrated around the face and scalp a few weeks to months after birth.12 For these reasons, we thought it was reasonable to consider a purpuric variant of neonatal lupus in addition to the traditional blueberry muffin rash differential diagnosis. Clinical speculating aside, we felt that a skin biopsy was important to help diagnose this infant’s rash.
Neonatal lupus was mentioned. Infants with neonatal lupus have antibodies that are transmitted from the mother. Our patient’s mother denied major illnesses. Is this common?
Dr Eyal Muscal (Pediatric Rheumatology)
Over 50% to 60% of mothers do not have a rheumatologic illness at the time of their infants being diagnosed with neonatal lupus. It is important to note that the condition is self-limited in infants and improvement is seen once the maternal antibodies dissipate in 4 to 6 months. The skin lesions are typically annular and can be scaly and erythematous. When these infants go out into the sun, they may develop a rash that percolates.
Other features of neonatal lupus include congenital heart block, transaminitis, and cytopenias. You can evaluate this diagnosis by sending lupus spectrum antibodies, such as immunoglobulin (Ig)G Sjögren’s syndrome autoantibodies (SSA [ro] SSB [La]), liver, and blood counts, and take a careful maternal history. As mentioned, however, many mothers may not have a history of a rheumatologic disease.
While on the pediatric hospital medicine service, laboratories, imaging, and skin biopsy were obtained for diagnostic evaluation. Infectious serologies are listed in Table 2 and were negative. In addition, a skeletal survey was normal. Liver function tests were normal, and a peripheral blood smear showed no hematologic malignancy. As noted in Table 1, there was a normal uric acid level, but lactate dehydrogenase was elevated to 2014 IU/L. An abdominal ultrasound was normal and without hepatosplenomegaly or adrenal lesions. An anti-nuclear antibody panel and testing for other rheumatologic antibodies were negative. Vanillylmandelic acid (VMA) and homovanillic acid (HVA) samples were sent as well, which returned negative.
Can you comment on why VMA and HVA samples were sent for this patient?
Urine catecholamines (VMA or HVA) are used as a biomarker for neuroblastoma. Approximately 80% to 90% of patients with neuroblastoma will have elevated urine VMA or HVA due to secretion of the catecholamine byproducts by the tumor.13 Thus, if it is positive, it is nearly pathognomonic for neuroblastoma, but the negative result does not rule it out.
As Dr Hunt suggested, a skin biopsy was important diagnostically for this patient, and results were finally obtained. What did it show under the microscope?
Dr Kalyani Patel (Pediatric Pathology)
On low-power view, the entire dermis and superficial subcutaneous fat are infiltrated by sheets of fairly monotonous and atypical blue cells (Fig 3). Immediately, a malignancy was highest on my differential. Extramedullary hematopoiesis can be a mimic, but is usually well organized and noninfiltrative.
High-power examination shows solid sheets of large cells with a high nucleus to cytoplasm ratio, irregular nuclear contours, fine chromatin, prominent nucleoli, and scattered hyperchromasia. Cytoplasmic borders are indistinct, giving a syncytial appearance (Fig 4). Several apoptotic bodies and mitotic figures are seen, which is indicative of a high proliferative index. The nuclear features are not typical for a small-round blue cell tumor, such as neuroblastoma, that has stippled chromatin and a spectrum of ganglionic differentiation. Ewing’s sarcoma is a possibility, but it is less likely in the absence of a mass elsewhere. The placenta was not available in this case to evaluate for the presence of these atypical cells in the fetal vessels.
Are there other staining techniques to help us determine the type of neoplasm?
Yes. The tumor cells were positive for myeloperoxidase and CD43 (Fig 5 A and B) which is essentially diagnostic of myeloid blasts and a myeloid sarcoma. Diffuse positivity for CD68 (PGM1 clone) was suggestive of monocytic differentiation and the M5 subcategory (Fig 5C). Tumor cells were negative for terminal deoxynucleotidyl transferase (lymphoblasts), CD1a (LCH), CD3 and CD5 (T-cell markers), Pax 5 (B-cell marker), CD30 (anaplastic large cell lymphoma), tryptase (mast cells), NB84a (neuroblastoma), CD99 (Ewing’s sarcoma), and pancytokeratin (epithelial malignancy).
This case is an interesting case of myeloid sarcoma. Can you tell us more about this diagnosis?
Dr Valeria Smith (Pediatric Hematology and Oncology)
Myeloid sarcoma is a rare neoplastic condition consisting of immature myeloid cells that form a tumor in an extramedullary site.14 Myeloid sarcomas were first described in the early 19th century, and, at that time, they were termed “chloromas” due to the green tumor appearance. Later, the term was changed to “granulocytic sarcoma” after several cases that lacked the green color of the tissue specimen, and they appeared more like a sarcoma.15 However, because we now know that not all myeloid leukemias are derived from granulocytes, the preferred term is myeloid sarcoma. Myeloid sarcoma can be single or multifocal and can be found in the skin, soft tissue, bone, lymph nodes, and, less commonly, the intestine, eyes, and mediastinum. It occurs in ∼11% of patients with acute myeloid leukemia (AML) when accounting for all extramedullary sites.16 It can occur de novo without AML or concurrently with AML. It can present several months to years before bone marrow evidence of leukemia, or it can be the first sign of relapse of leukemia. In our patient, a bone marrow biopsy was done that revealed 43% of cells were myeloid blasts and confirmed a diagnosis of AML with cutaneous myeloid sarcomas.
How does bone marrow involvement affect the treatment and prognosis of this condition?
The treatment is the same regardless of bone marrow involvement. Myeloid sarcoma was once felt to be more aggressive than traditional AML; however, we now believe that the specific biology of the particular AML subtype is more important for prognosis than the presence of myeloid sarcomas. The standard AML treatment is intensive chemotherapy with possible bone marrow transplantation (which is determined by biological factors and response to therapy). We have seen great improvements in the overall survival of patients with AML in the last 30 years, and the rate has doubled to nearly 65%.17 However, AML in infants often acts differently it does in older children, and the course can be difficult to predict.18
What are common signs and symptoms to help evaluate for leukemia in general pediatrics practice?
Leukemia, in general, is the most common childhood cancer. With regard to AML, ∼730 new cases are diagnosed each year in the United States in patients <20 years of age.19 Children with AML will typically present with some combination of the following: fever, fatigue, pain, pallor, weight loss, bony pain, anorexia, and malaise. Physical examination findings can include hepatosplenomegaly, excessive bruises (particularly areas that do not typically bruise), petechiae, or pallor. In an infant, the signs and symptoms may be more difficult to recognize and may be brought to the attention of the physician by the parent for poor feeding, decreased activity, increased fussiness, or prolonged fever without a source. Physical examination and laboratory findings may include an abnormal complete blood count, hepatosplenomegaly, petechiae, and other rashes, as seen in this case.17
How is the patient doing?
Dr Judith Margolin (Pediatric Hematology and Oncology)
He is doing well. The rest of his workup revealed CNS disease, which means that leukemia cells were present in the spinal fluid, and an MRI of the brain showed leukemia infiltrates. He received the first cycle of chemotherapy and experienced some anticipated side effects, such as neutropenia and mucositis, for which he received supportive care. After 1 cycle, he had a partial response and subsequently went into complete remission after a second cycle of chemotherapy. He is now 6 months’ postcompletion of all 4 cycles of chemotherapy and remains in complete remission and is meeting all of his developmental milestones.
We thank Gerardo Cabrera-Meza, MD, Eyal Muscal, MD, Kalyani Patel, MD, and Judith Margolin, MD.
- Accepted January 31, 2017.
- Address correspondence to John B. Darby, MD, Department of Pediatrics, Baylor College of Medicine/Texas Children’s Hospital, 1102 Bates Street, #FC1860, Houston, TX 77030. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they no potential conflicts of interest to disclose.
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- Copyright © 2017 by the American Academy of Pediatrics